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Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Colorectal cancer (CRC) exhibits the characteristics of familial clustering in ~10-15% of cases. The most common cause of hereditary CRC is Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC). LS is caused by a germline mutation in one of the genes within the DNA mismatch repair (MMR) system.

Tabs Content

Clinical Overview

Key Points

Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome that predisposes an individual to colorectal, endometrial, gastric, ovarian, upper urinary tract, and other cancers. Several organizations recommend universal screening of all colorectal cancer (CRC) specimens (American Gastroenterological Association [AGA], 2015; American Society of Clinical Oncology [ASCO], 2015; European Society for Medical Oncology [ESMO], 2013; National Comprehensive Cancer Network [NCCN], 2016; American Society for Clinical Pathology [ASCP]/College of American Pathologists [CAP]/Association for Molecular Pathology [AMP]/American Society of Clinical Oncology [ASCO], 2017) and all endometrial cancer patients (up to age 50, NCCN, 2016) for LS. In most situations, it is most effective to first evaluate specimens from suspected LS patients with immunohistochemistry (IHC) or polymerase chain reaction (PCR), as only 2-4% of CRCs are LS-associated (NCCN, 2016). However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to proceed to single or full-panel genetic testing.

Mismatch Repair Deficiency

Presence of mismatch repair (MMR) deficiency helps identify patients who may have LS – MMR testing should be ordered in all patients with CRC (ASCP/CAP/AMP/ASCO, 2017)

MMR deficiency also occurs in ~15% of sporadic CRCs

Definitive diagnosis of LS requires differentiating colorectal tumors with MMR deficiency due to a sporadic somatic event from colorectal tumors with MMR deficiency due to an LS germline mutation

MMR genes in which LS-causing mutations can occur

MLH1

MSH2

MSH6

PMS2

EPCAM (deletions causing methylation of MSH2)

Microsatellite Instability

Functions as a surrogate marker for MMR deficiency

Microsatellite instability (MSI) is caused by the loss of MMR activity

Screening and Diagnostic Testing

Screening and Diagnostic Testing for LS

Initial testinga

Typically, IHC or PCR testing is used initially to eliminate expense of full gene sequencing for the vast majority of tumors that lack MMR deficiency. Both tests are sensitive and usually produce concordant results. However, it is reasonable to proceed to germline multigene analysis instead if strong suspicion of LS exists (eg, family history, cancer at a young age).

Test

Test Interpretation

IHC

Involves staining of tumor tissue for protein expression of 4 MMR genes known to be mutated in LS (MLH1, MSH2, MSH6, and PMS2)

Background

Epidemiology

1/440 individuals in general population (American Gastroenterological Association [AGA], 2015)

2-4% of CRC (National Comprehensive Cancer Network [NCCN], 2016)

Age at presentation – mutation dependent (44-66 years mean)

>75% risk of developing CRC by 70 years

Sex – M:F, equal

Inheritance

Autosomal dominant with incomplete penetrance

Germline mutations in 1 of 4 DNA MMR genes

MLH1

MSH2

Small percentage of MSH2 inactivation is due to EPCAM deletions (included with MSH2 testing)

MSH6

PMS2

Inheritance of homozygous mutations for any of the above is termed biallelic MMR deficiency (BMMR-D)

MMR Gene Mutationsa

Common mutations

~90% of mutations in LS

MLH1 (mutL homolog1)

MSH2 (mutS homolog 2)

Less common mutations

MSH6 (mutS homolog 6)

PMS2 (postmeiotic segregation increased 2)

Heterodimeric complexes

Obligatory expression partners

MLH1 and PMS2

MLH1 mutation usually leads to concomitant PMS2 expression loss due to PMS2 degradation

MSH2 and MSH6

MSH2 mutation usually leads to concomitant MSH6 expression loss due to MSH6 degradation

MSH6 or PMS2 losses or mutations are usually not associated with any other loss

aMutations include point mutations and large genomic deletions or rearrangements

Clinical Presentation

Early onset of proximal (right side) CRC – often <50 years

Multiple metachronous and synchronous tumors are common

Early-onset extra colonic tumors – risk depends on mutation present (the following lifetime risk estimates apply to individuals with MLH1 and MSH2 pathogenic variants; risks for variants in MSH6 or PMS2 may be lower)

CRC – 52-82%

Endometrial – 25-60%

Some patients may present with endometrial tumor rather than colon tumor; some MSH6 germline-mutated families present with mainly endometrial tumors